Breast cancer patients with no response to tamoxifen may overcome resistance to the widely-used drug when taken in combination with the leukemia chemotherapy dasatinib, new research from the Kimmel Cancer Center at Jefferson suggests.
About 70% of breast cancer diagnoses are estrogen receptor (ER)–positive disease, which indicates that the tumor may respond to tamoxifen. However, up to 35% of these ER-positive tumors have little to no response to the drug or ultimately develop resistance to it.
Tamoxifen combined with dasatinib, a protein-tyrosine kinase inhibitor, reverses the chemoresistance caused by cancer-associated fibroblasts in the surrounding tissue by normalizing glucose intake and reducing mitochondrial oxidative stress, according to new research.
In this study, researchers explored the metabolic basis in an ER-positive cell line and cancer-associated fibroblasts to better understand drug resistance. Previously, the researchers determined a relationship between the two, where cancer cells generate aerobic glycolysis by secreting hydrogen peroxide in adjacent fibroblasts via oxidative stress. In turn, these fibroblasts provide nutrients to the cancer cells to proliferate. This process eventually makes tumors grow. This information led to an investigation and subsequent demonstration that this interaction was also the source of tamoxifen resistance.
The study showed that ER-positive cancer cells alone responded to tamoxifen. However, the drug had little to no effect, when cocultured with human fibroblasts. Likewise, dasatinib, a chemotherapy drug used to treat leukemia patients no longer benefiting from other medications, had no effect on fibroblasts alone or cancer cells. When tamoxifen and dasatinib were used together, however, the drug combination prevented the cancer cells cocultured with the fibroblasts from using high-energy nutrients from the fibroblasts.
This combination resulted in nearly 80% cell death, a 2- to 3-fold increase when compared with tamoxifen alone, the researchers reported.